7-55191757-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005228.5(EGFR):c.2508C>T(p.Arg836=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,613,938 control chromosomes in the GnomAD database, including 479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R836R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 32)
  • Exomes 𝑓: 0.022 (446 hom.)
• Consequence: EGFR NM_005228.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.31

Genes affected

EGFR (HGNC:3236): (epidermal growth factor receptor) The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. Mutations in this gene are associated with lung cancer. EGFR is a component of the cytokine storm which contributes to a severe form of Coronavirus Disease 2019 (COVID-19) resulting from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-55191757-C-T is Benign according to our data. Variant chr7-55191757-C-T is described in ClinVar as [Benign]. Clinvar id is 45281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-55191757-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.016 (2440/152134) while in subpopulation NFE AF= 0.0241 (1641/67998). AF 95% confidence interval is 0.0232. There are 33 homozygotes in gnomad4. There are 1190 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5	c.2508C>T	p.Arg836=	synonymous_variant	21/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.2508C>T	p.Arg836=	synonymous_variant	21/28	1	NM_005228.5	P1
EGFR	ENST00000455089.5	c.2373C>T	p.Arg791=	synonymous_variant	20/26	1
EGFR	ENST00000450046.2	c.2349C>T	p.Arg783=	synonymous_variant	21/28	4
EGFR	ENST00000700145.1	c.858C>T	p.Arg286=	synonymous_variant	8/9

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2441 AN: 152016 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00464

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0165 AC: 4153 AN: 251218 Hom.: 67 AF XY: 0.0166 AC XY: 2255 AN XY: 135764

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00376

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0219 AC: 31945 AN: 1461804 Hom.: 446 Cov.: 31 AF XY: 0.0212 AC XY: 15445 AN XY: 727208

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.00461

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00348

Gnomad4 FIN exome AF: 0.0356

Gnomad4 NFE exome AF: 0.0251

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0160 AC: 2440 AN: 152134 Hom.: 33 Cov.: 32 AF XY: 0.0160 AC XY: 1190 AN XY: 74368

Gnomad4 AFR AF: 0.00463

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0378

Gnomad4 NFE AF: 0.0241

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0178 Hom.: 15

Bravo AF: 0.0129

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0186

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 28, 2021	- -
Benign, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 24, 2007	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	This variant is associated with the following publications: (PMID: 24899223, 22192147) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -

EGFR-related lung cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Lung cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	1.4
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2229066; hg19: chr7-55259450; COSMIC: COSV51803130; COSMIC: COSV51803130;